Proposed are studies directed toward the synthesis of the pentacyclic guanidinium alkaloid crambescidin 816, the major constituent of the extracts of the red Caribbean sponge Crambe crambe. Crambescidin 816 displays a range of potentially significant biological activities including strong inhibition of the herpes simplex virus HSV-1, high activity against HCT-16 human colon carcinoma cells, and Ca++ antagonist behavior. However, the synthesis of crambescidin 816 has not been realized, due in large part to difficulty in installing the C13 hydroxyl group. The proposed approach to the synthesis of crambescidin 816 has, as its focal point, the highly diastereoselective [4+2] cycloaddition between an electron-deficient alkenyl carbodiimide and a chiral, 3,4-dihydro-2H-pyrrole that bears functionality at the imidoyl carbon atom. This approach allows for ready installation of masked hydroxyl functionality at what will become the C13 position of crambescidin 816 that can be revealed in a late stage of the synthesis. The long-term objectives of the proposed activities are to develop an efficient and flexible synthetic plan that will provide sufficient quantities of crambescidin 816 for thorough biological testing, will allow for the synthesis of related derivatives for the determination of structure-activity relationships, and that will be applicable to the synthesis of a range of guanidinium alkaloids such as crambescidins 830 and 844. Crambescidin 816 is the major constituent of the extracts of the red Caribbean sponge Crambe crambe and displays a range of potentially significant biological activities including antitumor and antiviral activity. The proposed studies will develop efficient and flexible synthetic routes that will provide sufficient quantities of crambescidin 816 for thorough biological testing, that will facilitate the synthesis of related biologically active molecules, and that will allow the structure-activity relationships of this important class of molecules to be investigated. [unreadable] [unreadable] [unreadable]